DESCRIPTION: Two recent studies found that trimethoprim-sulfamethoxazole (TS) prophylaxis reduced hospitalizations and mortality among HIV-infected persons in Cote d'Ivoire, and policies of widespread TS prophylaxis for HIV-infected individuals in Africa are under consideration. TS shares its mechanism of action with pyrimethamine-sulfadoxine (PS) and other antifolate drugs used to treat malaria, which is responsible for an estimated 2.7 million deaths in Africa each year. In vitro resistance to the antifolates in Plasmodium falciparum is caused by point mutations in the enzymes targeted by these drugs, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). In vitro studies suggest that TS prophylaxis will select for resistance-conferring DHFR and DHPS mutations in P. falciparum. Such selection could accelerate the development of Plasmodium falciparum resistance to PS and other antifolate antimalarials in areas where HIV infection and malaria are both highly prevalent. This accelerated resistance could occur both at the population level, and of more immediate concern, at the individual level, in that HIV-infected persons receiving TS prophylaxis who are or become infected with P. falciparum may be more likely to fail PS treatment and progress to severe disease and death. Antifolate-resistant Plasmodium falciparum malaria is increasing in the same Central and East African countries where HIV infection rates are highest, including Malawi, where PS has been the first-line antimalarial treatment since 1993. In addition to possible selection for antifolate resistant malaria, bacterial pathogens prevented by TS prophylaxis appear to be less susceptible to TS in Malawi. The potential impact of TS prophylaxis on antifolate-resistant malaria needs to be assessed quickly and definitively, and the benefit of TS prophylaxis demonstrated thus far in a single setting needs to be confirmed in settings with high malaria endemicity and different bacterial resistance profiles. The overall aims of this project are to determine whether the benefits of TS prophylaxis seen in Cote d'Ivoire can be confirmed in Malawi, and test the hypothesis that TS prophylaxis selects for anti-folate resistant P. falciparum. This will be accomplished in a prospective, double blinded, placebo-controlled trial in an area of Malawi with high rates of both HIV and malaria. Morbidity, mortality, PS-resistant malaria and anti-folate-resistant DHFR and DHPS genotypes will be measured in symptomatic HIV-infected adults receiving daily TS prophylaxis or placebo. These studies are expected to add to our basic knowledge of the molecular basis of antifolate-resistant malaria and provide information that will be of direct and immediate relevance to current HIV and malaria control policies in Africa.